The tail flick test is a test of the pain response in animals, similar to the hot plate test. It is used in basic pain research and to measure the effectiveness of analgesics, by observing the reaction to heat. It was first described by D'Amour and Smith in 1941. [1]
Most commonly, an intense light beam is focused on the animal's tail and a timer starts. When the animal flicks its tail, the timer stops and the recorded time (latency) is a measure of the pain threshold. [2] Alternate methods can be used to apply heat, such as immersion in hot water. [3]
Alternately, a dolorimeter with a resistance wire with a constant heat flow may be used. For the tail flick test, the wire is attached to the tail of the organism, and the wire applies heat to the tail. The researcher then records the latency to tail flick. [4]
Researchers testing the effectiveness of drugs on the pain threshold often use the tail flick test to measure the extent to which the drug being tested has reduced the amount of pain felt by the model organism. [5]
Both laboratory mice and rats are a common model organism for these tests. These rodents are usually given analgesics, which are responsible for weakening the response to pain. Under these weakened responses to pain, with effectiveness often peaking about 30 minutes after ingestion, researchers test the effectiveness of the drugs by exposing the tail to constant heat and measuring how long it takes to flick, signaling its response to the pain. [6] [7] Naloxone and naltrexone, two opioid antagonists, have been used to study pain sensitivity in relation to exercise in mice. [8]
Experimental tests of the tail flick testing method showed that the temperature of the skin of the tail plays a major role in the critical temperature, i.e., the temperature at which the tail flicks in response to pain. Researchers found that if the tail has been exposed to a cooler temperatures before the test, then the critical temperature decreases. [9]
Through use of the tail flick test, researchers have found that genetics play a role in pain sensation and the effectiveness of analgesics. A mouse of one genetic line may be more or less tolerant of pain than a mouse of another genetic line. Also, a mouse of one genetic line may experience a higher or lower effectiveness of an analgesic than a mouse of another genetic line. Using this test, researchers can also begin to identify genes that play a role in pain sensation. For example, the Calca gene (see WikiGenes CALCA) is primarily responsible for the variability in thermal (heat) nociception. [10] The Sprawling mutation (see WikiGenes Swl) resulted in a moderate sensory neuropathy but the mutation did not affect nociceptive modality or motor function in the mice. The mice with the Sprawling mutation were unable to sense the pain, but their other sensory functions were unaffected. [11]
The tail flick test is one test to measure heat-induced pain in animals. This reflexive response is an indicator of pain sensitivity in an organism and reduction of pain sensitivity produced by analgesics. Limitations of this test include: the need for more research with murine subjects, and determining the validity of applying observed pain responses from animals to humans. [12] Also, researchers have found that skin temperature can significantly affect the results of the tail flick test and it is important to consider this effect when performing the test. [13] Lastly, many thermal tests do not distinguish between opioid agonists and mixed agonist-antagonists, and consequently a tail flick test for mice using cold water in place of heat has been developed to allow that distinction. [14]
Dynorphins (Dyn) are a class of opioid peptides that arise from the precursor protein prodynorphin. When prodynorphin is cleaved during processing by proprotein convertase 2 (PC2), multiple active peptides are released: dynorphin A, dynorphin B, and α/β-neoendorphin. Depolarization of a neuron containing prodynorphin stimulates PC2 processing, which occurs within synaptic vesicles in the presynaptic terminal. Occasionally, prodynorphin is not fully processed, leading to the release of “big dynorphin.” “Big Dynorphin” is a 32-amino acid molecule consisting of both dynorphin A and dynorphin B.
Opioid receptors are a group of inhibitory G protein-coupled receptors with opioids as ligands. The endogenous opioids are dynorphins, enkephalins, endorphins, endomorphins and nociceptin. The opioid receptors are ~40% identical to somatostatin receptors (SSTRs). Opioid receptors are distributed widely in the brain, in the spinal cord, on peripheral neurons, and digestive tract.
Nociceptin/orphanin FQ (N/OFQ), a 17-amino acid neuropeptide, is the endogenous ligand for the nociceptin receptor. Nociceptin acts as a potent anti-analgesic, effectively counteracting the effect of pain-relievers; its activation is associated with brain functions such as pain sensation and fear learning.
The thromboxane receptor (TP) also known as the prostanoid TP receptor is a protein that in humans is encoded by the TBXA2R gene, The thromboxane receptor is one among the five classes of prostanoid receptors and was the first eicosanoid receptor cloned. The TP receptor derives its name from its preferred endogenous ligand thromboxane A2.
Opioid-induced hyperalgesia (OIH) or opioid-induced abnormal pain sensitivity, also called paradoxical hyperalgesia, is an uncommon condition of generalized pain caused by the long-term use of high dosages of opioids such as morphine, oxycodone, and methadone. OIH is not necessarily confined to the original affected site. This means that if the person was originally taking opioids due to lower back pain, when OIH appears, the person may experience pain in the entire body, instead of just in the lower back. Over time, individuals taking opioids can also develop an increasing sensitivity to noxious stimuli, even evolving a painful response to previously non-noxious stimuli (allodynia). This means that if the person originally felt pain from twisting or from sitting too long, the person might now additionally experience pain from a light touch or from raindrops falling on the skin.
Nav1.7 is a sodium ion channel that in humans is encoded by the SCN9A gene. It is usually expressed at high levels in two types of neurons: the nociceptive (pain) neurons at the dorsal root ganglion (DRG) and trigeminal ganglion; and sympathetic ganglion neurons, which are part of the autonomic (involuntary) nervous system.
The nociceptin opioid peptide receptor (NOP), also known as the nociceptin/orphanin FQ (N/OFQ) receptor or kappa-type 3 opioid receptor, is a protein that in humans is encoded by the OPRL1 gene. The nociceptin receptor is a member of the opioid subfamily of G protein-coupled receptors whose natural ligand is the 17 amino acid neuropeptide known as nociceptin (N/OFQ). This receptor is involved in the regulation of numerous brain activities, particularly instinctive and emotional behaviors. Antagonists targeting NOP are under investigation for their role as treatments for depression and Parkinson's disease, whereas NOP agonists have been shown to act as powerful, non-addictive painkillers in non-human primates.
Hypoalgesia or hypalgesia denotes a decreased sensitivity to painful stimuli.
Transient receptor potential cation channel subfamily M (melastatin) member 8 (TRPM8), also known as the cold and menthol receptor 1 (CMR1), is a protein that in humans is encoded by the TRPM8 gene. The TRPM8 channel is the primary molecular transducer of cold somatosensation in humans. In addition, mints can desensitize a region through the activation of TRPM8 receptors.
Transient receptor potential cation channel subfamily M member 3 is a protein that in humans is encoded by the TRPM3 gene.
Transient receptor potential cation channel, subfamily V, member 3, also known as TRPV3, is a human gene encoding the protein of the same name.
Tebanicline is a potent synthetic nicotinic (non-opioid) analgesic drug developed by Abbott. It was developed as a less toxic analog of the potent poison dart frog-derived compound epibatidine, which is about 200 times stronger than morphine as an analgesic, but produces extremely dangerous toxic side effects. Like epibatidine, tebanicline showed potent analgesic activity against neuropathic pain in both animal and human trials, but with far less toxicity than its parent compound. It acts as a partial agonist at neuronal nicotinic acetylcholine receptors, binding to both the α3β4 and the α4β2 subtypes.
Iodoresiniferatoxin (I-RTX) is a strong competitive antagonist of the Transient Receptor Potential Vanilloid 1 (TRPV1) receptor. I-RTX is derived from resiniferatoxin (RTX).
The Randall–Selitto test or paw pressure test is a technique for the measurement of the pain response in animals. It is used in basic pain research and to test the effectiveness of analgetics by observing the reaction to gradually increasing pressure on an inflamed paw. Pain is deemed to be present if the animal starts to exhibit the flight or struggle response.
The hot plate test is a test of the pain response in animals, similar to the tail flick test. Both hot plate and tail-flick methods are used generally for centrally acting analgesic, while peripherally acting drugs are ineffective in these tests but sensitive to acetic acid-induced writhing test.
The melanocortin 1 receptor (MC1R), also known as melanocyte-stimulating hormone receptor (MSHR), melanin-activating peptide receptor, or melanotropin receptor, is a G protein–coupled receptor that binds to a class of pituitary peptide hormones known as the melanocortins, which include adrenocorticotropic hormone (ACTH) and the different forms of melanocyte-stimulating hormone (MSH). It is coupled to Gαs and upregulates levels of cAMP by activating adenylyl cyclase in cells expressing this receptor. It is normally expressed in skin and melanocytes, and to a lesser degree in periaqueductal gray matter, astrocytes and leukocytes. In skin cancer, MC1R is highly expressed in melanomas but not carcinomas.
A nociception assay evaluates the ability of an animal, usually a rodent, to detect a noxious stimulus such as the feeling of pain, caused by stimulation of nociceptors. These assays measure the existence of pain through behaviors such as withdrawal, licking, immobility, and vocalization. The sensation of pain is not a unitary concept; therefore, a researcher must be conscious as to which nociception assay to use.
N-2′-Indolylnaltrexamine (INTA) is an opioid and derivative of β-naltrexamine. This molecule is loosely derived from the classical opioid morphine. This experimental drug candidate is under development as a κ-opioid receptor agonist for pain management with fewer adverse side effects. Preclinical study in mice showed potent analgesic effects with no tolerance or dependence. The mice also showed no adverse effects in the conditioned place aversion assay.
Pain is an aversive sensation and feeling associated with actual, or potential, tissue damage. It is widely accepted by a broad spectrum of scientists and philosophers that non-human animals can perceive pain, including pain in amphibians.
SR-16435 is a drug which acts as a potent partial agonist at both the μ-opioid receptor and nociceptin receptor. In animal studies it was found to be a potent analgesic, with results suggestive of reduced development of tolerance and increased activity against neuropathic pain compared to classic μ-selective agonists.